Sepsis is the systemic inflammatory response syndrome that occurs during infection. Its incidence is approximately 750,000 per year in the US with a mortality of 30 to 50% and an annual cost of $17 billion. When severe, sepsis is often associated with profound hypotension, massive vasodilatation, shock, and multiple organ failure. Patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, nearly all general anesthetics produce cardiovascular depression, which can be life threatening particularly in the setting of sepsis. Etomidate is an imidazole-based general anesthetic that is distinguished from other general anesthetics by its lesser effects on cardiovascular function. This would seem to make it an ideal anesthetic for use in critically ill patients with sepsis. However because etomidate binds with high affinity to 112-hydroxylase, it potently suppresses synthesis of adrenocortical steroids that are critical for the stress response during sepsis that serves to restore homeostasis and enhance survival. Such "chemical adrenalectomy" by etomidate precludes its administration by continuous infusion to maintain anesthesia or sedation and has raised concerns regarding the administration of even a single IV bolus dose for anesthetic induction in septic patients. We hypothesize that this side effect can be "designed out" of etomidate by removing a single atom in the drug that is thought to mediate high affinity binding to 112-hydroxylase, while maintaining etomidate's favorable anesthetic and cardiovascular-sparing properties. To test this, we have developed carbo-etomidate as the lead compound in a new class of highly potent pyrrole-based anesthetics. Preliminary data show that like etomidate, carbo- etomidate is a highly potent general anesthetic that enhances GABAA receptor function and maintains hemodynamic stability. However, its potency for inhibiting in vitro steroid synthesis by adrenocortical cells is three orders of magnitude lower than that of etomidate and it does not suppress in vivo Cortrosyn-stimulated steroid synthesis following IV bolus administration. These observations suggest that carbo-etomidate or similar analogues could be exceptionally safe anesthetic agents for use in septic critically ill patients who are already at high risk for adrenocortical insufficiency and death. As the first step toward testing this hypothesis and establishing the basis for future preclinical and clinical studies of promising novel pyrrole-based anesthetics, we propose pilot studies to define in a septic rat model the impact of carbo-etomidate infusions on the adrenocortical and cytokine response to sepsis (Aim 1) and hemodynamic stability (Aim 2). These results will be compared to those obtained using the two most commonly used IV anesthetics, propofol and etomidate. The successful development of novel etomidate analogues that spare cardiovascular function without suppressing adrenocortical steroid synthesis will significantly improve human health by permitting anesthesia to be induced and maintained more safely in critically ill patients, and particularly those with sepsis. PUBLIC HEALTH RELEVANCE: Critically ill patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, all general anesthetics have deleterious side effects that can be life threatening to such patients. We have developed a novel general anesthetic for use in septic critically ill patients that our preliminary data suggest could be safer than all currently available agents. The proposed studies will test this by defining its physiological actions in an experimental model of sepsis.